The role of non-classical MHC class I molecules in immune responses to Mycobacterium tuberculosis infection

非经典 MHC I 类分子在结核分枝杆菌感染免疫反应中的作用

基本信息

批准号：
10402266
负责人：
Chyung-Ru Wang
金额：
$ 56.74万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-14 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10402266
关键词：
Activities of Daily Living Adoptive Transfer Animal Model Antigen Presentation Antigens Attenuated Autoimmune Diseases Bacterial Model Biological Assay Biological Response Modifiers CD8-Positive T-Lymphocytes CD8B1 gene Characteristics Development Elements Equilibrium Exhibits Flow Cytometry Frequencies Future Gene Expression Profile Generations Genetic Glycopeptides HLA G antigen Histocompatibility Antigens Class I Homologous Gene Host Defense Human Immune response Immunity Immunodominant Antigens Immunologic Memory In Vitro Individual Interruption KLRD1 gene Kinetics Knowledge Lead MHC antigen Mediating Memory Modeling Mouse Strains Mucous Membrane Mus Mutant Strains Mice Mycobacterium Infections Mycobacterium tuberculosis Mycobacterium tuberculosis H37Rv Mycobacterium tuberculosis antigens Peptides Phenotype Play Population Predisposition Preventive vaccine Property Proteins Pulmonary Pathology Qa-1 Antigen Receptor Activation Regulatory T-Lymphocyte Role Surface T cell regulation T cell response T memory cell T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets T-cell receptor repertoire Thymus Gland Tuberculosis Vaccination Vaccines Virulent Virus Diseases Vitamin B Complex base cytotoxic CD8 T cells microorganism antigen mouse model mycobacterial novel peptide vaccination prevent protective efficacy receptor response transcriptome sequencing tuberculosis immunity vaccination against tuberculosis vaccination strategy vaccine candidate vaccine development vaccine strategy

项目摘要

PROJECT SUMMARY While current Mycobacterium tuberculosis (Mtb) vaccine development has primarily focused on CD4+ and MHC Ia-restricted CD8+ T cell responses, increasing evidence shows that non-conventional CD8+ T cells restricted by MHC Ib molecules can recognize diverse microbial antigens and contribute to protection against Mtb infection. For example, H2-M3, Qa-1/HLA-E, Qa-2/HLA-G, MR1, and CD1 have been implicated in the host immune response against Mtb in mice and/or humans. However, most of these studies have only examined the function of MHC Ib-restricted T cells during the primary response to Mtb infection. Given that several subsets of MHC Ib- restricted T cells exhibit "innate-like" T cell characteristics and undergo unique thymic selection, it is unclear whether and which MHC Ib-restricted CD8+ T cell population can mount a memory response during Mtb infection. Furthermore, some MHC Ib molecules also act as regulators of the immune responses aside from their role in antigen presentation. In particular, Qa-1 can regulate immune responses against Mtb through the interaction with inhibitory CD94/NKG2A receptors and regulatory CD8+ T cells. To better understand the diverse role of MHC Ib molecules play in immune responses against Mtb, this proposal seeks to determine whether the composition and function of MHC Ib-restricted CD8+ T cell subsets in the secondary response differs from the primary response, as well as how individual Qa-1-mediated regulatory mechanisms contribute to the immune response against Mtb. In Aim 1, we propose to compare the kinetics, function, and protective ability of MHC Ib- restricted CD8+ T cell responses during primary and secondary Mtb infection in mice, and evaluate the protective efficacy of vaccination with Qa-1/HLA-E-restricted Mtb peptides. We will use a novel vaccination and re- challenge model that allows for complete clearance of an attenuated Mtb strain prior to challenge with fully virulent Mtb to study memory responses. These studies will allow us to identify the dominant MHC Ib-restricted CD8+ T cells and the Mtb antigens they present during the secondary immune response, their ability to mediate protective immunity against Mtb, and peptide vaccination strategies to increase the frequency of these effector CD8+ T cells. In Aim 2, we propose to investigate the mechanisms by which Qa-1 regulates immune responses during Mtb infection, with a focus on how inhibitory CD94/NKG2A receptors and suppressive Qa-1-restricted CD8+ Tregs individually contribute to the regulation of T cell responses during Mtb infection. To study these mechanisms, we will use mouse strains with genetic interruption of Qa-1’s interaction with individual receptors. These studies will allow us to identify how Qa-1 is able contribute to the balance between effector and regulatory immune responses for better protective immunity against Mtb. The combined results from our studies will yield a better understanding of how MHC Ib molecules and MHC Ib-restricted T cells contribute to the overall immune response against Mtb, for the development of better future vaccine strategies.

项目概要目前结核分枝杆菌 (Mtb) 疫苗的开发主要集中在 CD4+ 和 MHC Ia 限制的 CD8+ T 细胞反应，越来越多的证据表明，非常规 CD8+ T 细胞受 Ia 限制 MHC Ib 分子可以识别多种微生物抗原并有助于防止 Mtb 感染。例如，H2-M3、Qa-1/HLA-E、Qa-2/HLA-G、MR1 和 CD1 与宿主免疫有关然而，大多数这些研究仅检查了其功能。 MHC Ib 限制性 T 细胞在对 Mtb 感染的初次反应期间的变化限制性T细胞表现出“先天样”T细胞特征并经历独特的胸腺选择，目前尚不清楚 Mtb 感染期间是否以及哪些 MHC Ib 限制性 CD8+ T 细胞群可以产生记忆反应。此外，一些 MHC Ib 分子除了在免疫反应中发挥作用外，还充当免疫反应的调节剂。特别是，Qa-1 可以通过相互作用调节针对 Mtb 的免疫反应。与抑制性 CD94/NKG2A 受体和调节性 CD8+ T 细胞更好地了解不同的作用。 MHC Ib 分子在针对 Mtb 的免疫反应中发挥作用，该提案旨在确定是否次级反应中 MHC Ib 限制性 CD8+ T 细胞亚群的组成和功能不同于主要反应，以及个体 Qa-1 介导的调节机制如何促进免疫针对 Mtb 的反应在目标 1 中，我们建议比较 MHC Ib- 的动力学、功能和保护能力。小鼠原发性和继发性 Mtb 感染期间限制 CD8+ T 细胞反应，并评估保护性 Qa-1/HLA-E 限制性 Mtb 肽疫苗接种的功效我们将使用新型疫苗接种并重新进行疫苗接种。挑战模型，允许在完全挑战之前完全清除减毒结核分枝杆菌菌株这些研究将使我们能够识别主要的 MHC Ib 限制性 Mtb。 CD8+ T 细胞和它们在二次免疫反应期间呈现的 Mtb 抗原，它们介导的能力针对 Mtb 的保护性免疫，以及增加这些效应子频率的肽疫苗接种策略在目标 2 中，我们建议研究 Qa-1 调节免疫反应的机制。在 Mtb 感染期间，重点关注抑制性 CD94/NKG2A 受体和抑制性 Qa-1-restricted CD8+ Tregs 单独参与 Mtb 感染期间 T 细胞反应的调节。机制，我们将使用 Qa-1 与个体受体相互作用的基因中断的小鼠品系。这些研究将使我们能够确定 Qa-1 如何促进效应器和调节器之间的平衡免疫反应，以获得更好的针对结核分枝杆菌的保护性免疫力我们研究的综合结果将产生。更好地了解 MHC Ib 分子和 MHC Ib 限制性 T 细胞如何促进整体免疫系统应对 Mtb，以制定更好的未来疫苗策略。